Although much evidence circumstantially implicates the brain cholinergic system in Alzheimer's disease (AD) dementia, the degree to which the cholinergic dysfunction can explain the features of the cognitive impairment is not known. We propose that examination of non-AD individuals also having brain cholinergic dysfunction is likely to significantly increase our understanding of the role of the brain cholinergic system in dementia. In this regard our MAJOR OBJECTIVE is to conduct a combined brain neurochemical, neuropathological, and behavioral study of 31 individuals from four well-studied families afflicted with a hereditary cerebellar disorder (dominantly-inherited olivopontocerebellar atrophy, OPCA). A preliminary neurochemical study of several members of each family revealed a cortical cholinergic deficiency as severe as that observed in end-stage AD. Surprisingly, none of the OPCA patients at last examination appeared grossly to have any clinically significant dementia. Our SPECIFIC AIMS are: 1) to assess carefully, once a year the cognitive (using a test battery approach) and neurological status of the 31 affected patients; 2) to examine systematically and extensively the behavioral of the major neurotrasnmitter systems (esp. cholinergic) in brain of the OPCA patients as they come to autopsy; and 3) to perform the first detailed neuropathological examination of extracerebellar brain areas in OPCA with special attention devoted to the quantitative assessment of the basal forebrain cholinergic nuclei. As shown below, all personnel have demonstrated expertise in their individual areas of research. An essential and special feature of this proposal will be the collaboration with Drs. Schut and Currier, who will arrange all patient contact with the investigators. Much effort is now being directed to the pharmacological restoration of cholinergic function in AD brain in an attempt to normalize cognitive process. A crucial question, which is directly related to the likelihood of success of this approach is whether the brain cholinergic degeneration in AD is in fact related to any clinically significant extent to the mental deterioration. We suggest that results of our intensive and careful examination of OPCA individuals may have profound implications with respect to 1) the actual role of the brain cholinergic system in human cognition and 2) prospects of successful cholinergic therapy in dementia disorders.